Identification of a Mutation in the Extracellular Domain of the Epidermal Growth Factor Receptor Conferring Cetuximab Resistance in Colorectal Cancer

Nat Med. 2012 Jan 22;18(2):221-3. doi: 10.1038/nm.2609.

Abstract

Antibodies against epidermal growth factor receptor (EGFR)--cetuximab and panitumumab--are widely used to treat colorectal cancer. Unfortunately, patients eventually develop resistance to these agents. We describe an acquired EGFR ectodomain mutation (S492R) that prevents cetuximab binding and confers resistance to cetuximab. Cells with this mutation, however, retain binding to and are growth inhibited by panitumumab. Two of ten subjects studied here with disease progression after cetuximab treatment acquired this mutation. A subject with cetuximab resistance harboring the S492R mutation responded to treatment with panitumumab.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Antibodies, Monoclonal / therapeutic use*
  • Antibodies, Monoclonal, Humanized
  • Antineoplastic Agents / therapeutic use*
  • Cell Line, Tumor
  • Cetuximab
  • Colorectal Neoplasms / drug therapy*
  • Colorectal Neoplasms / genetics
  • Drug Resistance, Neoplasm / genetics*
  • Epitopes / genetics
  • ErbB Receptors / genetics*
  • Gefitinib
  • Humans
  • Mutation, Missense / genetics
  • Panitumumab
  • Quinazolines / therapeutic use

Substances

  • Antibodies, Monoclonal
  • Antibodies, Monoclonal, Humanized
  • Antineoplastic Agents
  • Epitopes
  • Quinazolines
  • Panitumumab
  • ErbB Receptors
  • Cetuximab
  • Gefitinib